Concurrent chemoradiotherapy for squamous cell carcinoma of the anus using a shrinking field radiotherapy technique without a boost

Chemoradiotherapy (CRT) is now widely accepted as the primary treatment modality for squamous cell cancer of the anus. While randomised trials have clearly shown CRT to be more effective than radiotherapy alone, there remains uncertainty over the optimal integration of chemotherapy and radiation. We describe a series of 50 patients treated by a site specialist gastrointestinal nonsurgical oncologist with CRT at a single UK centre. Chemotherapy comprised mitomycin C (MMC) (day 1) and 5-fluorouracil (5-FU) (days 1–4, and 29–32), concurrent with 50 Gy in 25 fractions radiation, using a two-phase shrinking field technique. A radiation boost was not planned. At a median follow-up of 48 months, 11 (22%) of the patients have failed locally, of which three have been surgically salvaged. Nine (18%) have died of anal cancer. These results are comparable with those from large randomised studies, and suggest that a two-phase shrinking field radiotherapy technique with no boost, concurrent with MMC/5-FU chemotherapy, is an effective regimen for this disease. The CRT regimen described here provides the basis for the ‘control arm’ of the current UK-randomised CRT trial in anal cancer (ACT2)

Evaluation of Wuchereria bancrofti GST as a Vaccine Candidate for Lymphatic Filariasis

Lymphatic parasites survive for years in a complex immune environment by adopting various strategies of immune modulation, which includes counteracting the oxidative free radical damage caused by the host. We now know that the filarial parasites secrete antioxidant enzymes. Among these, the glutathione-S-transferases (GSTs) have the potent ability to effectively neutralize cytotoxic products arising from reactive oxygen species (ROS) that attack cell membranes. Thus, GSTs have the potential to protect the parasite against host oxidative stress. GSTs of several helminthes, including schistosomes, fasciola and the filarial parasite Seteria cervi, are also involved in inducing protective immunity in the host. The schistosome 28 kDa GST has been successfully developed into a vaccine and is currently in Phase II clinical trials. Thus, GST appears to be a potential target for vaccine development. Therefore, in the present study, we cloned W. bancrofti GST, and expressed and purified the recombinant protein. Immunization and challenge experiments showed that 61% of protection could be achieved against B. malayi infections in a jird model. In vitro studies confirm that the anti-WbGST antibodies participate in the killing of B. malayi L3 through an ADCC mechanism and enzymatic activity of WbGST appears to be critical for this larvicidal function

The Origin and Initial Rise of Pelagic Cephalopods in the Ordovician

BACKGROUND: During the Ordovician the global diversity increased dramatically at family, genus and species levels. Partially the diversification is explained by an increased nutrient, and phytoplankton availability in the open water. Cephalopods are among the top predators of today's open oceans. Their Ordovician occurrences, diversity evolution and abundance pattern potentially provides information on the evolution of the pelagic food chain. METHODOLOGY/PRINCIPAL FINDINGS: We reconstructed the cephalopod departure from originally exclusively neritic habitats into the pelagic zone by the compilation of occurrence data in offshore paleoenvironments from the Paleobiology Database, and from own data, by evidence of the functional morphology, and the taphonomy of selected cephalopod faunas. The occurrence data show, that cephalopod associations in offshore depositional settings and black shales are characterized by a specific composition, often dominated by orthocerids and lituitids. The siphuncle and conch form of these cephalopods indicate a dominant lifestyle as pelagic, vertical migrants. The frequency distribution of conch sizes and the pattern of epibionts indicate an autochthonous origin of the majority of orthocerid and lituitid shells. The consistent concentration of these cephalopods in deep subtidal sediments, starting from the middle Tremadocian indicates the occupation of the pelagic zone early in the Early Ordovician and a subsequent diversification which peaked during the Darriwilian. CONCLUSIONS/SIGNIFICANCE: The exploitation of the pelagic realm started synchronously in several independent invertebrate clades during the latest Cambrian to Middle Ordovician. The initial rise and diversification of pelagic cephalopods during the Early and Middle Ordovician indicates the establishment of a pelagic food chain sustainable enough for the development of a diverse fauna of large predators. The earliest pelagic cephalopods were slowly swimming vertical migrants. The appearance and early diversification of pelagic cephalopods is interpreted as a consequence of the increased food availability in the open water since the latest Cambrian

Developmental Transcriptomic Features of the Carcinogenic Liver Fluke, Clonorchis sinensis

Clonorchis sinensis is the causative agent of the life-threatening disease endemic to China, Korea, and Vietnam. It is estimated that about 15 million people are infected with this fluke. C. sinensis provokes inflammation, epithelial hyperplasia, and periductal fibrosis in bile ducts, and may cause cholangiocarcinoma in chronically infected individuals. Accumulation of a large amount of biological information about the adult stage of this liver fluke in recent years has advanced our understanding of the pathological interplay between this parasite and its hosts. However, no developmental gene expression profiles of C. sinensis have been published. In this study, we generated gene expression profiles of three developmental stages of C. sinensis by analyzing expressed sequence tags (ESTs). Complementary DNA libraries were constructed from the adult, metacercaria, and egg developmental stages of C. sinensis. A total of 52,745 ESTs were generated and assembled into 12,830 C. sinensis assembled EST sequences, and then these assemblies were further categorized into groups according to biological functions and developmental stages. Most of the genes that were differentially expressed in the different stages were consistent with the biological and physical features of the particular developmental stage; high energy metabolism, motility and reproduction genes were differentially expressed in adults, minimal metabolism and final host adaptation genes were differentially expressed in metacercariae, and embryonic genes were differentially expressed in eggs. The higher expression of glucose transporters, proteases, and antioxidant enzymes in the adults accounts for active uptake of nutrients and defense against host immune attacks. The types of ion channels present in C. sinensis are consistent with its parasitic nature and phylogenetic placement in the tree of life. We anticipate that the transcriptomic information on essential regulators of development, bile chemotaxis, and physico-metabolic pathways in C. sinensis that presented in this study will guide further studies to identify novel drug targets and diagnostic antigens

Cathelicidin-like Helminth Defence Molecules (HDMs) Absence of Cytotoxic, Anti-microbial and Anti-protozoan Activities Imply a Specific Adaptation to Immune Modulation

Host defence peptides (HDPs) are expressed throughout the animal and plant kingdoms. They have multifunctional roles in the defence against infectious agents of mammals, possessing both bactericidal and immune-modulatory activities. We have identified a novel family of molecules secreted by helminth parasites (helminth defence molecules; HDMs) that exhibit similar structural and biochemical characteristics to the HDPs. Here, we have analyzed the functional activities of four HDMs derived from Schistosoma mansoni and Fasciola hepatica and compared them to human, mouse, bovine and sheep HDPs. Unlike the mammalian HDPs the helminth-derived HDMs show no antimicrobial activity and are non-cytotoxic to mammalian cells (macrophages and red blood cells). However, both the mammalian- and helminth-derived peptides suppress the activation of macrophages by microbial stimuli and alter the response of B cells to cytokine stimulation. Therefore, we hypothesise that HDMs represent a novel family of HDPs that evolved to regulate the immune responses of their mammalian hosts by retaining potent immune modulatory properties without causing deleterious cytotoxic effects. © 2013 Thivierge et al

Ebola: translational science considerations

We are currently in the midst of the most aggressive and fulminating outbreak of Ebola-related disease, commonly referred to as “Ebola”, ever recorded. In less than a year, the Ebola virus (EBOV, Zaire ebolavirus species) has infected over 10,000 people, indiscriminately of gender or age, with a fatality rate of about 50%. Whereas at its onset this Ebola outbreak was limited to three countries in West Africa (Guinea, where it was first reported in late March 2014, Liberia, where it has been most rampant in its capital city, Monrovia and other metropolitan cities, and Sierra Leone), cases were later reported in Nigeria, Mali and Senegal, as well as in Western Europe (i.e., Madrid, Spain) and the US (i.e., Dallas, Texas; New York City) by late October 2014. World and US health agencies declared that the current Ebola virus disease (EVD) outbreak has a strong likelihood of growing exponentially across the world before an effective vaccine, treatment or cure can be developed, tested, validated and distributed widely. In the meantime, the spread of the disease may rapidly evolve from an epidemics to a full-blown pandemic. The scientific and healthcare communities actively research and define an emerging kaleidoscope of knowledge about critical translational research parameters, including the virology of EBOV, the molecular biomarkers of the pathological manifestations of EVD, putative central nervous system involvement in EVD, and the cellular immune surveillance to EBOV, patient-centered anthropological and societal parameters of EVD, as well as translational effectiveness about novel putative patient-targeted vaccine and pharmaceutical interventions, which hold strong promise, if not hope, to curb this and future Ebola outbreaks. This work reviews and discusses the principal known facts about EBOV and EVD, and certain among the most interesting ongoing or future avenues of research in the field, including vaccination programs for the wild animal vectors of the virus and the disease from global translational science perspective